The leukocyte group 5 antigenic system has two dominant alleles (5a and 5b) which segregate independently of HLA. We have discovered that the 5a allele of this system has a striking association with acute lymphoblastic leukemia (ALL), the strongest association yet found of an antigen with human leukemia. In subsequent studies, the 5a allele was also found to be associated with chronic lymphocytic leukemia and lymphocytic lymphoma but not with histiocytic lymphoma or with Hodgkin's disease. We propose, by use of the leukocyte agglutination and antibody-dependent cell-mediated cytotoxicity assays, to: (1)\study the association of 5a with ALL in an attempt to gain insight into the cause of ALL; (2)\determine the significance of the 5a antigen as a prognostic marker; (3)\study patients with other hematological disorders for increased frequencies of the 5a and 5b alleles; and (4)\attempt to assign the group 5 locus to a particular linkage group.